In silico design of a multi-epitope vaccine against the triple negative breast cancer
Mohammad Zahraei1, Esmaeil Roohparvar Basmenj2, Gholamreza Behrouzi3
1Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. mhdzahrayee@yahoo.com.
Abstract:
Triple-negative breast cancer (TNBC) represents a particularly aggressive subtype of breast cancer lacking expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2), leading to restricted treatment options and unfavorable outcomes and prognosis. This research employs immunoinformatics and reverse vaccinology strategies to develop novel multi-epitope protein and mRNA vaccines targeting TNBC-associated antigens. By using a detailed scoring system, we identified seven extracellular proteins (TROP-2, EpCAM, MUC1, NECTIN4, Folate Receptor α, Mesothelin, α-Lactalbumin) and two intracellular proteins (MAGE-A, NY-ESO-1) as targets for the vaccine. Through a thorough process of predicting and validating epitopes, we discovered 18 MHC-I epitopes, 1 MHC-II epitope, and 2 B-cell epitopes with considerable binding affinity and population coverage (87.75% for the Persian-Iranian cohort), with an emphasis on the MHC-I pathway. The constructed protein vaccine demonstrated favorable physicochemical characteristics, structural stability, non-toxicity, and non-allergenic potential. TLR4 was found to be the primary pattern recognition receptor for adjuvant interaction, and molecular docking illustrated strong binding strength. In constructing the mRNA vaccine, we included N-5' m7GCap, 5' UTR, Kozak sequence, signal peptide (tPA), MHC epitopes, linker, MITD sequence, stop codon, 3' UTR, and poly-A tail. Consequently, the design of the mRNA vaccine integrated optimized codon sequences with relevant regulatory components, achieving a Codon Adaptation Index of 0.93. Furthermore, we propose an innovative four-part mRNA vaccine approach to balance therapeutic effectiveness with clinical practicalities. Both vaccine formulations showed intense immune stimulation in silico, indicating their potential as promising candidates for immunotherapy against TNBC, which will require further experimental exploration.
Insights
Researchers developed novel multi-epitope protein and mRNA vaccines targeting triple-negative breast cancer (TNBC) antigens. These vaccines show promise for immunotherapy, with potential for high population coverage and strong immune stimulation in silico.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis.
- Current therapies for TNBC are restricted due to the absence of ER, PR, and HER2 expression.
Purpose of the Study:
- To design and develop novel multi-epitope protein and mRNA vaccines against TNBC using immunoinformatics and reverse vaccinology.
- To identify and validate potential TNBC-associated antigens and their corresponding epitopes for vaccine development.
Main Methods:
- Utilized immunoinformatics and reverse vaccinology to identify TNBC-associated extracellular and intracellular antigens.
- Predicted and validated MHC-I, MHC-II, and B-cell epitopes with high binding affinity and population coverage.
- Constructed and characterized protein and mRNA vaccine candidates, including assessment of physicochemical properties, adjuvant interaction via TLR4, and codon optimization for mRNA.
Main Results:
- Identified nine potential TNBC target antigens (seven extracellular, two intracellular).
- Discovered 18 MHC-I, 1 MHC-II, and 2 B-cell epitopes with 87.75% population coverage.
- Developed stable, non-toxic, and non-allergenic protein vaccine and a highly optimized mRNA vaccine (Codon Adaptation Index of 0.93).
- Demonstrated strong binding affinity with TLR4 and significant in silico immune stimulation for both vaccine types.
Conclusions:
- The developed protein and mRNA vaccines are promising candidates for TNBC immunotherapy.
- The novel four-part mRNA vaccine approach offers a balance of therapeutic efficacy and clinical practicality.
- Further experimental validation is warranted to confirm the therapeutic potential of these in silico-designed vaccines.
More Related Videos
07:59A High Throughput MHC II Binding Assay for Quantitative Analysis of Peptide Epitopes
Published on: March 25, 2014
07:33Preparation, Characteristics, Toxicity, and Efficacy Evaluation of the Nasal Self-Assembled Nanoemulsion Tumor Vaccine In Vitro and In Vivo
Published on: September 28, 2022